Francesc X. Soriano, Sangeeta Chawla, Paul Skehel and Giles E. Hardingham SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites Journal of Neurochemistry 124
Nuclear export of repressors is an important mechanism of transcriptional regulation. Class IIa HDACs are known to exit the nucleus in Ca2+ dependent manner by CaM Kinase-dependent phosphorylation (a). Here we uncover, in cortical neurons, a novel mechanism of class IIa HDAC nuclear export which is independent of CaM Kinase-dependent phosphorylation, mediated by co-shuttling with co-repressor SMRT. SMRT's class IIa HDAC-interacting domain RD3 is key for co-shuttling (b). We go on to show that this finding is physiologically relevant in the BDNF signaling (c). We find that BDNF promotes the direct nuclear import of HDAC5, but the nuclear export of SMRT. The effect of SMRT-mediated HDAC5 co-shuttling means that the presence of SMRT effectively prevents BDNF-induced direct HDAC5 import. (a) Phospho-mutant forms of class IIa HDACs cannot be exported by Ca2+ signals. (b) SMRT renders phospho-mutant forms of HDACs exportable by Ca2+ signals. (c) SMRT-mediated HDAC5 export opposes BDNF-induced HDAC5 nuclear accumulation.
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